1,2,5-Thiadiazocan-7-one 1,1-dioxides — a novel charted region in the chemical space of 8-membered azasultams

Abstract

Herein, we describe an efficient and cost-effective synthesis of previously unreported 1,2,5-thiadiazocan-7-one 1,1-dioxides through the CSIC (Carbanion-mediated Sulfonate (Sulfonamide) Intermolecular Coupling (Intramolecular Cyclization) reaction strategy. These compounds belong to a small family of 8-membered cyclic sulfonamides, possessing an additional endocyclic nitrogen atom and therefore abbreviated as azasultams (a portmanteau of aza + sulfa lactam). The target azasultams were prepared in a few simple steps and in good overall yield from readily available reagents. Particularly, the alkylation of NH-heteroaryl carboxylates with N,O-dimesylated β-aminoalcohols gave the corresponding 1-(2-(N-methylsulfonamido)ethyl)-1H-heteroaroyl-2-carboxylates, which underwent base-mediated sulfa-Dieckmann condensation affording the target 8-membered azasultams. To demonstrate the synthetic utility of 1,2,5-thiadiazocan-7-one 1,1-dioxides, a few derivatizations were attempted, thereby expanding the limited chemical space of the relatively underrepresented 8-membered azasultams. The combined NMR and X-ray diffraction study, supported by DFT calculations, allowed us to investigate the structural features of functionalized 1,2,5-thiadiazocane 1,1-dioxides, formulate the structure-activity relationship, and estimate the strain energy. Finally, the molecular docking study predicted a strong binding affinity of the selected azasultams to cancer-associated receptors, which are therapeutic targets in cancer treatment.